CN102249939A - Lipid-water amphiphilic benzylidene cyclopentanone dye and preparation method and application in photodynamic therapy thereof - Google Patents
Lipid-water amphiphilic benzylidene cyclopentanone dye and preparation method and application in photodynamic therapy thereof Download PDFInfo
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Abstract
The invention relates to a lipid-water amphiphilic benzylidene cyclopentanone dye, a preparation method and an application in photodynamic therapy thereof. The invention provides a compound with a general formula (I), wherein R1 is a -(C2H4O)m-R5 group; and the definitions of R2, R3, R4 are as defined in the specification. The compound with the general formula (I) of the invention has a simple structure, a low molecular weight, a determined chemical structure, and a lipid-water amphiphilic property, is easy to prepare, purify and further modify, and meets basic requirements of clinical medication. The lipid-water amphiphilic benzylidene cyclopentanone dye of the invention can generate singlet oxygen and superoxide anions under the irradiation of a light source with a wave band range of 350-600 nm, and has good application prospects in the aspect of photodynamic medicament preparation.
Description
Technical field
The invention belongs to field of photodynamic, particularly relate to the preparation method of the amphipathic benzylidene cyclopentanone of lipoid water dyestuff and the purposes in optical dynamic therapy thereof.
Technical background
Optical dynamic therapy is a kind of emerging tumor therapeuticing method; its treatment principle is by behind system or topical application photosensitizers; laser radiation with specific wavelength; generation singlet oxygen etc. has phototoxic material; at the selective killing of " original position " realization to target tissue; but have advantages such as good, traumatic little, the safe repetitive therapy of selectivity; can protect appearance and the function of safeguarding vitals to greatest extent, in clinical cancer therapy, obtain many achievements that attract people's attention.In recent years, optical dynamic therapy also is widely used in the treatment of the optimum common disease of the effective methods of treatment of many shortages, as belong to the nevus flammeus and the senile fundus macular degeneration of capillary blood vessel class disease, and become clinical first-selection or unique specific short of this type of disease, expanded the Application Areas of optical dynamic therapy greatly.
At present; the photosensitizers that can be used for the photodynamic tumor treatment mainly contains hematoporphyrin derivative, glycyl propionic acid, chlorin, metal phthalocyanine, benzoporphyrin derivative, DESAY's porphyrin etc.; be entitled as " clinical tumor optical dynamic therapy " referring to the Liao Wangjun chief editor; the People's Medical Officer Press, ISBN number is the books of 7-5091-023-2.These photosensitizerss exist all that in various degree active princlple is unclear, purity is not high, killing-efficiency is low, internal metabolism waits shortcoming slowly.With respect to the LASER Light Source and the light conduction technique of fast development, the exploitation of photo-dynamical medicine becomes the bottleneck problem of restriction optical dynamic therapy clinical application.
For a long time, optical dynamic therapy is primarily aimed at the treatment of noumenal tumour, in order to guarantee that incident light is woven with enough penetration depths to tumor group, " optical dynamic therapy window " with tumour is defined in the 600-900nm scope in the world, and the ruddiness in this wavelength region is about 5-10mm to the penetration depth of tumour.Yet, the not enough 1mm of the focus degree of depth of capillary blood vessel class disease, obviously, this kind disease is used the photosensitizers of 600-900nm red light absorption can reduce drug effect on the contrary or deep tissues is damaged, use the light source in the 450-550nm wavelength region then more to be complementary with the focus of capillary blood vessel class disease, can bring into play drug effect and reduction damage to greatest extent, referring to Chinese patent application publication number CN101235004A to healthy tissues.Therefore, should be the new strategy of optical dynamic therapy method according to cultivating one's individuality of focus characteristics novel drugs.In addition, need carry out in the pathology of double-photon optical photodynamic therapy,, realize killing and wounding, also need to treat in conjunction with the single photon method than the photodynamics of big area focus in order to improve the speed of laser irradiation at some.
Summary of the invention
One object of the present invention is that the benzylidene cyclopentanone dyestuff that provides a lipoid water amphipathic, such dyestuff have simple, the synthetic characteristics that are easy to of molecular structure.
Another object of the present invention is to provide lipoid water parents, and its fat water dispenser is than the benzylidene cyclopentanone dyestuff that can satisfy clinical optical dynamic therapy service requirements.
A further object of the present invention is to provide the preparation method of the amphipathic benzylidene cyclopentanone dyestuff of a kind of fat water, and that this method has is simple to operate, can high-volume synthesize product yield height, the characteristics that purity is high.
Another purpose of the present invention is to provide the purposes of the amphipathic benzylidene cyclopentanone dyestuff of a kind of fat water, such dyestuff has stronger absorption in 350～600nm wavelength region, singlet oxygen, superoxide anion isoreactivity oxygen species can be produced under the light source irradiation in 350～600nm wavelength region fast, optical dynamic therapy can be used for.
Another purpose of the present invention provides a kind of can replenishing mutually with double-photon optical photodynamic therapy method, unites the single photon optical dynamic therapy method of use.
The invention provides the compound of a kind of general formula (I):
Wherein: R
1For-(C
2H
4O)
m-R
5Group;
R
2For methyl, ethyl or-(C
2H
4O)
n-R
6Group;
R
3For methyl, ethyl or-(C
2H
4O)
p-R
7Group;
R
4For methyl, ethyl or-(C
2H
4O)
q-R
8Group;
R
1, R
2, R
3And R
4It can be identical or different substituted radical;
Described-(C
2H
4O)
m-R
5M=3 in the group, 4,5,6,7 or 8, preferred 4 or 5; R
5Be methyl, ethyl, propyl group or sec.-propyl, preferable methyl;
Described-(C
2H
4O)
n-R
6N=3 in the group, 4,5,6,7 or 8, preferred 4 or 5; R
6Be methyl, ethyl, propyl group or sec.-propyl, preferable methyl;
Described-(C
2H
4O)
p-R
7P=3 in the group, 4,5,6,7 or 8, preferred 4 or 5; R
7Be methyl, ethyl, propyl group or sec.-propyl, preferable methyl;
Described-(C
2H
4O)
q-R
8Q=3 in the group, 4,5,6,7 or 8, preferred 4 or 5; R
8Be methyl, ethyl, propyl group or sec.-propyl, preferable methyl.
The invention provides the preparation method of the amphipathic benzylidene cyclopentanone dyestuff of a kind of fat water, may further comprise the steps:
(1) have tosic acid fat A synthetic of polyoxyethylene glycol PEG group, reaction equation is as follows:
Wherein: x=2,3,4,5,6 or 7, preferred 3 or 4; R
9Be methyl, ethyl, propyl group or sec.-propyl, preferable methyl.
Concrete steps:
Reference literature, be people's such as Arthur Snow be entitled as " Conversion of alcohols to thiols viatosylate intermediates ", Synthesis, 2003, vol.4, synthetic method in the pp509-512 article adds a certain amount of NaOH in three mouthfuls of reactors and quality is its water of 5～20 times, stirs.Then, in the above-mentioned NaOH aqueous solution, add PEG in the ratio of PEG and NaOH mol ratio 1: 1～5 and volume is the tetrahydrofuran (THF) mixing solutions of 1～10 times of PEG volume.Use the ice bath temperature control, after stirring also logical nitrogen half an hour under 0～5 ℃ is with abundant deoxygenation, with molar weight is that the Tosyl chloride of 0.5～1 times of PEG amount is dissolved in the tetrahydrofuran (THF) that volume is 1～5 times of a PEG volume, and this tetrahydrofuran solution slowly is added drop-wise in above-mentioned three mouthfuls of reaction vessels that added PEG, tetrahydrofuran (THF) and the NaOH aqueous solution.Remove ice bath in reaction under 0～10 ℃ after 2～6 hours, continue reaction 4～12 hours under the room temperature.The reaction solution extracted with diethyl ether, the ether extraction liquid water is washed to neutrality, drying, filters, revolves to steam and remove the p-toluenesulfonic esters A that ether is connected with the PEG group accordingly, and is standby.
Wherein, the siccative of using in the above-mentioned drying operation is one or more the combination in anhydrous sodium sulphate, anhydrous magnesium sulfate, the Calcium Chloride Powder Anhydrous.
(2) have benzaldehyde derivative E synthetic of PEG group, reaction equation:
Wherein: R
10Be methyl or ethyl;
R
1For-(C
2H
4O)
m-R
5Group;
R
2For methyl, ethyl or-(C
2H
4O)
n-R
6Group;
R
1And R
2It can be identical or different substituted radical;
Described-(C
2H
4O)
m-R
5M=3 in the group, 4,5,6,7 or 8, preferred 4 or 5; R
5Be methyl, ethyl, propyl group or sec.-propyl, preferable methyl;
Described-(C
2H
4O)
n-R
6N=3 in the group, 4,5,6,7 or 8, preferred 4 or 5; R
6Be methyl, ethyl, propyl group or sec.-propyl, preferable methyl;
Concrete steps:
(i) reference literature, be people such as Thomas Bouder be entitled as " Synthesis and coordinationstudies of new mono-and di-hydroxy functionalized4; 4 '-dialkeny1-2; 2 '-bipyridines ", Tetrahedron letters, 1998, vol.39, synthetic method in the pp6869-6872 article, the adding mol ratio is 1: 2～5 N in three mouthfuls of reactors, N-dihydroxy ethyl aniline and diacetyl oxide (Ac
2O), adding molar weight after mixing again is N, the pyridine that N-dihydroxy ethyl aniline is 2～5 times.With above-mentioned mixed solution at N
2Reflux is 2～10 hours under the atmosphere, and cooling is revolved to steam and removed low-boiling point material diacetyl oxide and pyridine, and 188～190 ℃/0.1MP cut is collected in underpressure distillation, obtains golden yellow oily liquids, i.e. intermediate product B.
(ii) a certain amount of intermediate product B of adding and quality are its N of 2～5 times in there-necked flask, and dinethylformamide (DMF) stirs and makes its dissolving evenly.With molar weight is 1～2 times the phosphorus oxychloride (POCl of intermediate product B
3) to be added drop-wise to quality in 0～5 ℃ be POCl
32～10 times DMF in, stirring reaction slowly was added drop-wise to it in above-mentioned there-necked flask after 1～10 hour, after dropwising, temperature of reaction was risen to 50～150 ℃ and stirring reaction 2～10 hours, cooling back impouring Na
2CO
3Molar weight is POCl
35～20 times, concentration be the Na of 0.5～2mol/L
2CO
3In the frozen water solution, stirred 12～48 hours, the solid collected by filtration product gets faint yellow solid, i.e. intermediate product C.
(iii) reference literature, be people's such as Matthew Davis be entitled as " Solvent-free claisencondensation of isophorone and verbenone with para-hydroxyethylaminobenzaldehydes ", Synthetic Communications, 2007, vol.37, synthetic method in the pp921-926 article, above-mentioned intermediate product C is dissolved in quality in its methyl alcohol of 1～5 times, the molar weight that under agitation adds NaOH is 2～5 times of intermediate product C, concentration is the NaOH aqueous solution of 5～20mol/L, continue to stir 2～10 hours, stopped reaction, reaction solution is revolved steaming remove methyl alcohol, use the dichloromethane extraction water, the dichloromethane extraction liquid that obtains is washed with water to neutrality, drying, filter, revolve to steam and remove methylene dichloride and obtain yellow oily liquid 4-(N, N-two (2-hydroxyl-ethyl) amino) phenyl aldehyde.
Wherein, the siccative of using in the above-mentioned drying operation is one or more the combination in anhydrous sodium sulphate, anhydrous magnesium sulfate, the Calcium Chloride Powder Anhydrous.
(iv) reference literature, be people's such as Christian B.Nielsen be entitled as " Synthesis andcharacterization of water-soluble phenylene-vinylene-based singlet oxygensensitizers for two-photon excitation ", The Journal of Organice Chemistry, 2005, vol.70, synthetic method in the pp7065-7079 article, with 4-(N, N-two (2-hydroxyl-ethyl) amino) phenyl aldehyde or the commercial Compound D that can get, be 4-(N-methyl-N-(2-hydroxyl-ethyl) amino) phenyl aldehyde or 4-(N-ethyl-N-(2-hydroxyl-ethyl) amino) phenyl aldehyde, be dissolved in quality for its 10～30 times in the tetrahydrofuran (THF) (THF) that super-dry is heavily steamed, slowly add molar weight then and be in the solution that the potassium hydroxide of 1～5 times of above-mentioned benzaldehyde derivative and the THF through super-dry is heavily steamed that quality is 10～30 times of above-mentioned benzaldehyde derivatives mix, reaction mixture is at N
2After stirring half an hour under the atmosphere, reflux 1～5 hour obtains intermediate reaction liquid.With molar weight is that the intermediate product A of 1～5 times of above-mentioned benzaldehyde derivative slowly is added dropwise in the above-mentioned intermediate reaction liquid, continued reflux 12～48 hours, cooling, end reaction liquid is neutralized to neutrality with acid, use dichloromethane extraction, drying, filter, revolve to steam and obtain thick product after removing methylene dichloride, separate to purify obtaining yellow oily liquid with chromatographic column, promptly have the benzaldehyde derivative E of PEG group.
Wherein, the acid of using in the above-mentioned neutralization operation is dilute hydrochloric acid or dilute sulphuric acid below the 1mol/L for concentration; The siccative of using in the above-mentioned drying operation is one or more the combination in anhydrous sodium sulphate, anhydrous magnesium sulfate, the Calcium Chloride Powder Anhydrous.
(3) have the amphipathic dyestuff H of fat water synthetic of PEG group, reaction equation:
Wherein: R
11Be methyl or ethyl;
R
12Be methyl or ethyl;
Preferred R
11And R
12Be identical substituting group;
R
1Be selected from-(C
2H
4O)
m-R
5Group;
R
2Be selected from methyl, ethyl or-(C
2H
4O)
n-R
6Group;
R
3Be selected from methyl, ethyl or-(C
2H
4O)
p-R
7Group;
R
4Be selected from methyl, ethyl or-(C
2H
4O)
q-R
8Group;
R
1, R
2, R
3And R
4It can be identical or different substituted radical;
Described-(C
2H
4O)
m-R
5M=3 in the group, 4,5,6,7 or 8, preferred 4 or 5; R
5Be selected from methyl, ethyl, propyl group or sec.-propyl;
Described-(C
2H
4O)
n-R
6N=3 in the group, 4,5,6,7 or 8, preferred 4 or 5; R
6Be selected from base, ethyl, propyl group or sec.-propyl;
Described-(C
2H
4O)
p-R
7P=3 in the group, 4,5,6,7 or 8, preferred 4 or 5; R
7Be selected from methyl, ethyl, propyl group or sec.-propyl;
Described-(C
2H
4O)
q-R
8Q=3 in the group, 4,5,6,7 or 8, preferred 4 or 5; R
8Be selected from methyl, ethyl, propyl group or sec.-propyl.
(i) with cyclopentanone and the benzaldehyde derivative E or the compound F 17-hydroxy-corticosterone that have the PEG group, the for example commercial 4-(N that can get, the N-dimethylamino) phenyl aldehyde or 4-(N, the N-diethylin) phenyl aldehyde, according to mol ratio is that 1: 1～2 ratio adds reaction vessel, adding quality then is 10～30 times the ethanol-water solution (wherein the alcoholic acid volumn concentration is 20%～80%) of E or F, adding molar weight again is 0.01～0.4 times the basic catalyst of E or F, under 0 ℃ of condition, reacted 2～10 hours, remove ice bath, reaction is 1～5 hour under the room temperature condition, obtains thick product through filtering or revolving to steam except that desolvating, and separates to purify obtaining intermediate product G with chromatographic column.
Be that 1: 1～2 ratio adds reaction vessel according to mol ratio (ii) with above-mentioned intermediate product G and the benzaldehyde derivative E that has a PEG group, adding quality then is 10～30 times the alcohol solvent of E, add molar weight again and be the basic catalyst of 0.01～0.4 times of the molar weight of E, under 25～80 ℃ of conditions, reacted 5～40 hours, obtain thick product through the overwinding steaming except that desolvating, separate to purify obtaining target dyestuff H of the present invention with chromatographic column.
Be that 1: 2～5 ratio adds reaction vessel according to mol ratio (iii) with cyclopentanone and the benzaldehyde derivative E that has a PEG group, adding quality then is 10～30 times the alcohol solvent of E, add molar weight again and be the basic catalyst of 0.01～0.4 times of the molar weight of E, under 25～80 ℃ of conditions, reacted 5～40 hours, obtain thick product through the overwinding steaming except that desolvating, separate to purify obtaining target dyestuff H of the present invention with chromatographic column.
Above-mentioned basic catalyst can be a kind of in sodium hydroxide, potassium hydroxide, anhydrous sodium carbonate, Anhydrous potassium carbonate, the hexahydropyridine or two or more mixture arbitrarily in them.
The amphipathic benzylidene cyclopentanone dyestuff of fat water of the present invention all has fat water parents' character, and along with the increase of PEG group quantity and the growth of chain length, the wetting ability of dyestuff increases.
The amphipathic benzylidene cyclopentanone dyestuff of fat water of the present invention has stronger absorption in 350～600nm wavelength region.
Can produce singlet oxygen, superoxide anion isoreactivity oxygen species fast under the amphipathic light source irradiation of benzylidene cyclopentanone dyestuff in 350～600nm wavelength region of fat water of the present invention, have good application prospects aspect the preparation photo-dynamical medicine.
The present invention has following characteristics:
1. the amphipathic benzylidene cyclopentanone of the fat water dye structure among the present invention is simple, molecular weight is little, has definite chemical structure, is easy to preparation, purifying and further modification, satisfies the basic demand of clinical application.
2. the amphipathic benzylidene cyclopentanone of the fat water dyestuff among the present invention has fat water parents' characteristics, and its fat water dispenser is than the service requirements that can satisfy clinical optical dynamic therapy.
3. the preparation method of the amphipathic benzylidene cyclopentanone dyestuff of fat water has characteristics simple to operate, that product yield is high, purity is high among the present invention, can high-volume synthesize.
4. the amphipathic benzylidene cyclopentanone dyestuff of the fat water among the present invention has higher biological photodynamic activity in 350～600nm wavelength region, has good application prospects aspect the preparation photo-dynamical medicine.
Description of drawings
Fig. 1 illustrates the absorption spectrum of dyestuff in n-Octanol and PBS buffered soln among the embodiment 1.
Fig. 2 illustrates the singlet oxygen signal that produces by dyestuff among the detected embodiment 1 of ESR in dimethyl sulfoxide (DMSO).
Fig. 3 illustrates the superoxide anion free radical signal that produces by dyestuff among the detected embodiment 1 of ESR in dimethyl sulfoxide (DMSO).
Fig. 4 illustrates the singlet oxygen phosphorescent emissions spectrum that dyestuff produces among the embodiment 1 that detects by the infrared optical fiber spectrograph in n-Octanol under the 473nm laser radiation.
Fig. 5 illustrates the absorption spectrum of dyestuff in n-Octanol and PBS buffered soln among the embodiment 2.
Fig. 6 illustrates the singlet oxygen phosphorescent emissions spectrum that dyestuff produces among the embodiment 2 that detects by the infrared optical fiber spectrograph in n-Octanol under the 473nm laser radiation.
Fig. 7 illustrates the singlet oxygen signal that produces by dyestuff among the detected embodiment 3 of ESR in dimethyl sulfoxide (DMSO).
Fig. 8 illustrates the absorption spectrum of dyestuff in n-Octanol and PBS buffered soln among the embodiment 4.
Fig. 9 illustrates the singlet oxygen phosphorescent emissions spectrum that dyestuff produces among the embodiment 4 that detects by the infrared optical fiber spectrograph in n-Octanol under the 532nm laser radiation.
Figure 10 illustrates the superoxide anion free radical signal that produces by dyestuff among the detected embodiment 5 of ESR in dimethyl sulfoxide (DMSO).
Figure 11 illustrates the absorption spectrum of dyestuff in n-Octanol and PBS buffered soln among the embodiment 6.
Figure 12 illustrates the singlet oxygen signal that produces by dyestuff among the detected embodiment 7 of ESR in dimethyl sulfoxide (DMSO).
Figure 13 illustrates the absorption spectrum of dyestuff in n-Octanol and PBS buffered soln among the embodiment 8.
Figure 14 illustrates the singlet oxygen phosphorescent emissions spectrum that dyestuff produces among the embodiment 8 that detects by the infrared optical fiber spectrograph in n-Octanol under the 473nm laser radiation.
Figure 15 illustrates the wavelength of the absorption peak correspondence of dyestuff H1-H8 in n-Octanol and PBS buffered soln among the embodiment 1-8, the data such as singlet oxygen quantum yield in n-Octanol.
Embodiment
The invention will be further described below in conjunction with specific embodiment, but the present invention is not limited to following examples.
Embodiment 1
(i) add 8 gram (0.2mol) NaOH in 250 milliliters of there-necked flasks, 40 ml waters stir and make its dissolving evenly.Mix with NaOH solution dissolving evenly in 14.42 gram (0.12mol) two poly glycol monomethyl ethers 30 milliliters of tetrahydrofuran (THF)s of adding (THF), adding then in the above-mentioned there-necked flask.22.88 gram (0.12mol) Tosyl chlorides and 40 milliliters of THF are mixed, slowly be added dropwise to then in the above-mentioned there-necked flask, the dropping process keeps reacting liquid temperature to be no more than 10 ℃, after dropwising, continues stirring reaction 4 hours, stopped reaction.Reaction solution is with extracted with diethyl ether three times, and extraction liquid washes with water to neutrality and adds anhydrous sodium sulfate drying, after filtration, revolve to steam and remove ether, obtain 30.2 grams (productive rate: corresponding p-toluenesulfonic esters Al 92%),
1HNMR (400MHz CDCl
3): δ (ppm) 2.42 (s, 3H), 3.32 (s, 3H), 3.45 (t, J=2.4Hz, 2H), 3.52 (t, J=2.2Hz, 2H), 3.65 (t, J=4.8Hz, 2H), 4.14 (t, J=4.0Hz, 2H), 7.31 (d, J=8.2Hz, 2H), 7.77 (d, J=6.8Hz, 2H).
(ii) in 250 milliliters of there-necked flasks, add 25 gram (0.138mol) N, N-dihydroxy ethyl aniline, 31 gram (0.31mol) diacetyl oxides and 25 gram (0.356mol) pyridines mix back reflux 2 hours under nitrogen protection.Be cooled to room temperature, revolve to steam and remove low-boiling point material diacetyl oxide and pyridine, 188～190 ℃/0.1MP cut is collected in underpressure distillation, obtains 34.6 gram (productive rate 94.5%) golden yellow oily liquids intermediate product B,
1HNMR (400MHz CDCl
3): δ (ppm) 2.05 (s, 6H), 3.72 (t, J=6.2Hz, 4H), 4.28 (t, J=6.2Hz, 4H), 6.65～6.70 (m, 3H), 7.19 (d, J=7.3Hz, 2H).
(iii) add 34.6 gram (0.131mol) intermediate product B and 100 milliliters of N in 500 milliliters of there-necked flasks, dinethylformamide (DMF) stirs.With 22 gram (0.144mol) phosphorus oxychloride (POCl
3) be added drop-wise among 100 milliliters 0～5 ℃ the DMF, stirring reaction slowly was added drop-wise to it in above-mentioned there-necked flask after 2 hours, after dropwising, reacting liquid temperature was risen to 150 ℃ and stirring reaction 2 hours, and cooling back impouring contains 60 gram Na
2CO
32 liters of frozen water solution in, stirred 48 hours, have a large amount of solids to generate, the solid collected by filtration product gets faint yellow solid 34 gram (productive rate 89%) intermediate product C,
1HNMR (400MHz CDCl
3): δ (ppm) 2.04 (s, 6H), 3.70 (t, J=6.2Hz, 4H), 4.27 (t, J=6.2Hz, 4H), 6.82 (d, J=8.8Hz, 2H), 7.75 (d, J=8.8Hz, 2H), 9.76 (s, 1H).
(iv) in 500 milliliters of there-necked flasks, add 19.5 gram (0.067mol) intermediate product C and 50 ml methanol, stir and make its dissolving evenly.5.33 gram (0.133mol) NaOH are dissolved in 10 ml waters, slowly add in the above-mentioned there-necked flask, stirring reaction 2 hours, stopped reaction revolves steaming with reaction solution and removes methyl alcohol, uses the dichloromethane extraction water, the dichloromethane extraction liquid that obtains is washed with water to neutral back and adds anhydrous sodium sulfate drying, after filtration, revolve to steam and remove methylene dichloride and obtain 13.6 gram (productive rate 97.8%) yellow oily liquid 4-(N, N-two (2-hydroxyl-ethyl) amino) phenyl aldehydes
1HNMR (400MHz CDCl
3): δ (ppm) 3.32 (bs, 2H), 3.71 (t, J=4.9Hz, 4H), 3.93 (t, J=4.9Hz), 6.72 (d, J=8.9Hz, 2H), 7.70 (d, J=8.9Hz, 2H), 9.70 (s, 1H).
(v) with 2.75 gram (0.013mol) 4-(N, N-two (2-hydroxyl-ethyl) amino) phenyl aldehyde is dissolved in 50 milliliters in the THF that super-dry is heavily steamed, slowly add 1.68 gram (0.03mol) KOH and 50 milliliters of solution that THF mixes then, dropwise, reaction solution is at N
2Reheat refluxed 1 hour after stirring half an hour under the atmosphere, obtained intermediate reaction liquid.8.16 gram (0.03mol) p-toluenesulfonic esters Al are dissolved among 20 milliliters of THF, slowly be added dropwise in the above-mentioned intermediate reaction liquid, continued reflux 48 hours, after the cooling, end reaction liquid is neutralized to neutrality with dilute hydrochloric acid, use dichloromethane extraction, extraction liquid through anhydrous magnesium sulfate drying, filter, revolve to steam and obtain thick product after removing methylene dichloride, separate to purify obtaining 3.78 gram (productive rate 71%) yellow oily liquid E1 with chromatographic column.
1HNMR(400MHz?CDCl
3)：δ(ppm)3.35(s，6H)，3.53～3.65(m，24H)，6.73(d，J＝9Hz，2H)，7.67(d，J＝9Hz，2H)，9.70(s，1H)。
(vi) in 100 milliliters of there-necked flasks, add 20.75 gram (0.05mol) E1,2.1 gram (0.025mol) cyclopentanone and 40 milliliters of ethanol, stirring makes the evenly disposable adding 0.25 gram KOH in back of its dissolving, heating made reaction mixture refluxed 5 hours, stop to heat the question response liquid cooling but after revolve to steam and remove ethanol and obtain thick product, separate to purify obtaining 15.71 gram (productive rate 72%) target dyestuff H1 of the present invention with chromatographic column.
1HNMR(400MHz?CDCl
3)：δ(ppm)3.06(s，4H)3.38(s，12H)3.52～3.61(m，48H)6.74(d，J＝8.5Hz，4H)7.49(d，J＝8.5Hz，6H).HR-MS(ESI)：m/z?Calcd?forC
47H
75N
2O
13[M+H]
+?875.52636；found?875.52309.
(vii) use PBS (pH=7.4) buffered soln to detect the solubleness of target dyestuff H1 in aqueous systems, 25 ℃ of its maxima solubilities reach more than the 1mg/ml.Target dyestuff H1 is dissolved in respectively in n-Octanol and the PBS buffered soln, tests its absorption spectrum, as shown in Figure 1, dyestuff H1 has stronger absorption peak in 350～600 wavelength regions.
(viii) use 5-N-oxide compound (DMPO) as singlet oxygen (
1O
2) the spin trapping agent, at the paramagnetic resonance spectrogram of the above-mentioned target dyestuff H1 of test in dimethyl sulfoxide (DMSO) (DMSO) under the 532nm laser excitation, obtain contour triplet as shown in Figure 2, its hyperfine splitting constant alpha and g-factor (g=2.0056, α
N=16.3G) and DMPO-
1O
2Adducts coincide, and illustrates that dyestuff H1 has produced singlet oxygen with the oxygen effect under 532nm laser excitation.
(ix) use 2,2,6,6-tetramethyl--4-piperidone (TEMP) is as superoxide radical (O
2 -) the spin trapping agent, at the paramagnetic resonance spectrogram of the above-mentioned target dyestuff H1 of test in dimethyl sulfoxide (DMSO) (DMSO) under the 532nm laser excitation, obtain quartet as shown in Figure 3, its hyperfine splitting constant alpha and g-factor (g=2.0056, α
N=12.48G,
) and TEMP-
2 -Adducts coincide, and illustrates that dyestuff H1 has produced superoxide radical with the oxygen effect under 532nm laser excitation.
(x) above-mentioned target dyestuff H1 is dissolved in to be configured to concentration in the n-Octanol be 2 * 10
-4The solution of M, in the dark logical oxygen detected the singlet oxygen phosphorescence spectrum by the infrared optical fiber spectrograph after 15 minutes under the 473nm laser radiation, obtain spectrogram shown in Figure 4, and the peak at 1270nm place is the phosphorescent emissions peak that ground state is returned in the singlet oxygen transition.Illustrate that dyestuff H1 has produced singlet oxygen under 473nm laser excitation condition.
Embodiment 2
(i) add 8 gram (0.2mol) NaOH in 250 milliliters of there-necked flasks, 80 ml waters stir and make its dissolving evenly.Mix with NaOH solution dissolving evenly among 50 milliliters of THF of 19.7 gram (0.12mol) three poly glycol monomethyl ethers addings, adding then in the above-mentioned there-necked flask.22.88 gram (0.12mol) Tosyl chlorides and 40 milliliters of THF are mixed, slowly be added dropwise to then in the above-mentioned there-necked flask, the dropping process keeps reacting liquid temperature to be no more than 10 ℃, after dropwising, continues stirring reaction 6 hours, stopped reaction.Reaction solution is with extracted with diethyl ether three times, and ether extraction liquid washes with water to neutrality and adds anhydrous magnesium sulfate drying, after filtration, revolve to steam and remove ether, obtain 34.7 grams (productive rate: corresponding p-toluenesulfonic esters A2 91%),
1HNMR (400MHz CDCl
3): δ (ppm) 2.42 (s, 3H), 3.34 (s, 3H), 3.49 (t, J=2.4Hz, 2H), 3.55 (m, 6H), 3.65 (t, J=4.8Hz, 2H), 4.11 (t, J=4.0Hz, 2H), 7.31 (d, J=8.1Hz, 2H), 7.75 (d, J=6.7Hz, 2H).
(ii), obtain yellow oily liquid 4-(N, N-two (2-hydroxyl-ethyl) amino) phenyl aldehyde with reference to embodiment 1 operation (ii)-(iv).With reference among the embodiment 1 (operation v) is 2: 1 p-toluenesulfonic esters A2 and the reaction of 4-(N, N-two (2-hydroxyl-ethyl) amino) phenyl aldehyde with molar weight, and preparation has the benzaldehyde derivative E2 of two PEG groups accordingly, productive rate 79%,
1HNMR (400MHz CDCl
3): δ (ppm) 3.36 (s, 6H), 3.52～3.63 (m, 32H), 6.71 (d, J=9Hz, 2H), 7.66 (d, J=9Hz, 2H), 9.68 (s, 1H).
(iii) with reference among the embodiment 1 (operation vi) is 2: 1 E2 and cyclopentanone reaction with molar weight, preparation target dyestuff H2, productive rate 61%,
1HNMR (400MHz CDCl
3): δ (ppm) 3.06 (s, 4H) 3.38 (s, 12H) 3.52～3.61 (m, 64H) 6.74 (d, J=8.7Hz, 4H) 7.49 (d, J=8.7HZ, 6H) .HR-MS (ESI): m/z Calcd for C
55H
91N
2O
17[M+H]
+1051.63122; Found 1051.63098.
(iv) use PBS (pH=7.4) buffered soln to detect the solubleness of target dyestuff H2 in aqueous systems, 25 ℃ of its maxima solubilities reach more than the 1mg/ml.Target dyestuff H2 is dissolved in respectively in n-Octanol and the PBS buffered soln, tests its absorption spectrum, as shown in Figure 5, dyestuff H2 has stronger absorption peak in 350～600 wavelength regions.
(v) (operation viii)-(x), the result has proved that equally target dyestuff H2 can produce singlet oxygen under 473nm or 532nm laser radiation, sees accompanying drawing 6, and superoxide anion with reference to embodiment 1.
Embodiment 3
(i) with reference among the embodiment 1 (operation v) is 1: 1 p-toluenesulfonic esters Al and the reaction of 4-(N-methyl-N-(2-hydroxyl-ethyl) amino) phenyl aldehyde with molar weight, and preparation has the benzaldehyde derivative E3 of a PEG group accordingly, productive rate 75%,
1HNMR (400MHz CDCl
3): δ (ppm) 3.07 (s, 3H), 3.34 (s, 3H), 3.51～3.65 (m, 12H), 6.71 (d, J=9Hz, 2H), 7.69 (d, J=9Hz, 2H), 9.70 (s, 1H).
(ii) with reference among the embodiment 1 (operation vi) is 2: 1 E3 and cyclopentanone reaction with molar weight, preparation target dyestuff H3, productive rate 72%,
1HNMR (400MHz CDCl
3): δ (ppm) 3.05 (s, 6H) 3.08 (s, 4H) 3.37 (s, 6H) 3.51～3.67 (m, 24H) 6.73 (d, J=8.6Hz, 4H) 7.51 (d, J=8.6Hz, 6H) .HR-MS (ESI): m/z Calcd for C
35H
51N
2O
7[M+H]
+611.36908; Found611.36926.
(iii) use PBS (pH=7.4) buffered soln to detect the solubleness of target dyestuff H3 in aqueous systems, 25 ℃ of its maxima solubilities reach more than the 0.1mg/ml.Target dyestuff H3 is dissolved in respectively in n-Octanol and the PBS buffered soln, tests its absorption spectrum, proved that dyestuff H3 has stronger absorption peak in 350～600 wavelength regions.
(iv) (operation viii)-(x), the result has proved that equally target dyestuff H3 can produce singlet oxygen under 473nm or 532nm laser radiation, sees accompanying drawing 7, and superoxide anion with reference to embodiment 1.
Embodiment 4
(i) with reference among the embodiment 1 (operation v) is 1: 1 p-toluenesulfonic esters A2 and the reaction of 4-(N-methyl-N-(2-hydroxyl-ethyl) amino) phenyl aldehyde with molar weight, and preparation has the benzaldehyde derivative E4 of a PEG group accordingly, productive rate 72%,
1HNMR (400MHz CDCl
3): δ (ppm) 3.09 (s, 3H), 3.36 (s, 3H), 3.52～3.68 (m, 16H), 6.73 (d, J=8.8Hz, 2H), 7.68 (d, J=8.8Hz, 2H), 9.70 (s, 1H).
(ii) with reference among the embodiment 1 (operation vi) is 2: 1 E4 and cyclopentanone reaction with molar weight, preparation target dyestuff H4, productive rate 72%,
1HNMR (400MHz CDCl
3): δ (ppm) 3.05 (s, 6H) 3.07 (s, 4H) 3.36 (s, 6H) 3.51～3.67 (m, 32H) 6.72 (d, J=8.5Hz, 4H) 7.49 (d, J=8.5Hz, 6H) .HR-MS (ESI): m/z Calcd for C
39H
59N
2O
9[M+H]
+699.42151; Found699.42167.
(iii) use PBS (pH=7.4) buffered soln to detect the solubleness of target dyestuff H4 in aqueous systems, 25 ℃ of its maxima solubilities reach more than the 1mg/ml.Target dyestuff H4 is dissolved in respectively in n-Octanol and the PBS buffered soln, tests its absorption spectrum, proved that dyestuff H4 has stronger absorption peak in 350～600 wavelength regions, see accompanying drawing 8.
(iv) (operation viii)-(x), the result has proved that equally target dyestuff H4 can produce singlet oxygen under 473nm or 532nm laser radiation, sees accompanying drawing 9, and superoxide anion with reference to embodiment 1.
Embodiment 5
(i) in 100 milliliters of there-necked flasks, add 8.85 gram (0.05mol) 4-(N, the N-diethylin) phenyl aldehyde, 4.2 gram (0.05mol) cyclopentanone, 30 milliliters of ethanol and 10 ml waters stir and make evenly 0.1 milliliter of piperidines of the disposable adding in back of its dissolving, and stirring reaction is 2 hours under the room temperature, there are a large amount of orange precipitations to separate out, orange precipitation is come out by filtering separation, and drying obtains thick product, with chromatographic column separate purify 5.1 gram (productive rate 42%) orange solids G1.
1HNMR(400MHz?CDCl3)：δ(ppm)1.19(t，J＝7.2Hz，6H)，2.04(m，2H)，2.34(t，2H)，2.95(t，2H)，3.40(q，J＝7.2Hz，4H)，6.69(d，J＝8.5Hz，2H)，7.51(d，J＝8.5Hz，3H)。
(ii) in 100 milliliters of there-necked flasks, add 10.3 gram (0.025mol) E1,6.08 gram (0.025mol) G1,40 milliliters of ethanol and 10 ml waters, stirring makes evenly 0.1 milliliter of piperidines of the disposable adding in back of its dissolving, 70 ℃ of following stirring reactions 8 hours revolve after the question response liquid cooling but to steam and remove the second alcohol and water and obtain thick product, separate to purify obtaining target dyestuff H5 with chromatographic column, productive rate 69%
1HNMR (400MHzCDCl
3): δ (ppm) 1.19 (t, J=7.2Hz, 6H) 3.05 (s, 4H) 3.37 (s, 6H) 3.43 (q, J=7.2Hz, 4H) 3.53～3.65 (m, 24H) 6.74 (d, J=8.6Hz, 4H) 7.52 (d, J=8.6Hz, 6H) .HR-MS (ESI): m/z Calcd for C
37H
55N
2O
7[M+H]
+639.40038; Found 639.40072.
(iii) use PBS (pH=7.4) buffered soln to detect the solubleness of target dyestuff H5 in aqueous systems, 25 ℃ of its maxima solubilities reach more than the 0.1mg/ml.Target dyestuff H5 is dissolved in respectively in n-Octanol and the PBS buffered soln, tests its absorption spectrum, proved that dyestuff H5 has stronger absorption peak in 350～600 wavelength regions.
(iv) (operation viii)-(x), the result has proved that equally target dyestuff H5 can produce singlet oxygen and superoxide anion under 473nm or 532nm laser radiation, see accompanying drawing 10 with reference to embodiment 1.
Embodiment 6
(i) with reference to (ii) operation among the embodiment 5, be 1: 1.1 G1 and E2 reaction with molar weight, preparation target dyestuff H6, productive rate 65%,
1HNMR (400MHz CDCl
3): δ (ppm) 1.20 (t, J=7.3Hz, 6H) 3.05 (s, 4H) 3.37 (s, 6H) 3.41 (q, J=7.2Hz, 4H) 3.53～3.65 (m, 32H) 6.71 (d, J=8.5Hz, 4H) 7.50 (d, J=8.5Hz, 6H) .HR-MS (ESI): m/z Calcd for C
41H
63N
2O
9[M+H]
+727.45281; Found 727.45418.
(ii) use PBS (pH=7.4) buffered soln to detect the solubleness of target dyestuff H6 in aqueous systems, 25 ℃ of its maxima solubilities reach more than the 1mg/ml.Target dyestuff H6 is dissolved in respectively in n-Octanol and the PBS buffered soln, tests its absorption spectrum, proved that dyestuff H6 has stronger absorption peak in 350～600 wavelength regions, see accompanying drawing 11.
(iii) (operation viii)-(x), the result has proved that equally target dyestuff H6 can produce singlet oxygen and superoxide anion under 473nm or 532nm laser radiation with reference to embodiment 1.
Embodiment 7
(i) with reference to (ii) operation among the embodiment 5, be 1: 1.2 G1 and E3 reaction with molar weight, preparation target dyestuff H7, productive rate 65%,
1HNMR (400MHz CDCl
3): δ (ppm) 1.21 (t, J=7.2Hz, 6H), 3.05 (s, 3H) 3.07 (s, 4H) 3.37 (s, 3H) 3.43 (q, J=7.2Hz, 4H), 3.52～3.67 (m, 12H) 6.69 (d, J=8.5Hz, 4H), 7.51 (d, J=8.5Hz, 6H) .HR-MS (ESI): m/z Calcd forC
31H
43N
2O
4[M+H]
+507.32173; Found 507.32192.
(ii) use PBS (pH=7.4) buffered soln to detect the solubleness of target dyestuff H7 in aqueous systems, 25 ℃ of its maxima solubilities reach more than the 0.1mg/ml.Target dyestuff H7 is dissolved in respectively in n-Octanol and the PBS buffered soln, tests its absorption spectrum, proved that dyestuff H7 has stronger absorption peak in 350～600 wavelength regions.
(iii) (operation viii)-(x), the result has proved that equally target dyestuff H7 can produce singlet oxygen under 473nm or 532nm laser radiation, sees accompanying drawing 12, and superoxide anion with reference to embodiment 1.
Embodiment 8
(i) with reference to (ii) operation among the embodiment 5, be 1: 1.5 G1 and E4 reaction with molar weight, preparation target dyestuff H8, productive rate 72%,
1HNMR (400MHz CDCl
3): δ (ppm) 1.21 (t, J=7.2Hz, 6H) 3.05 (s, 3H) 3.07 (s, 4H) 3.37 (s, 3H) 3.41 (q, J=7.2Hz, 4H) 3.52～3.67 (m, 16H) 6.71 (d, J=8.4Hz, 4H), 7.51 (d, J=8.4Hz, 6H) .HR-MS (ESI): m/z Calcd forC
33H
47N
2O
5[M+H]
+551.34795found 551.34846.
(ii) use PBS (pH=7.4) buffered soln to detect the solubleness of target dyestuff H8 in aqueous systems, 25 ℃ of its maxima solubilities reach more than the 0.1mg/ml.Target dyestuff H8 is dissolved in respectively in n-Octanol and the PBS buffered soln, tests its absorption spectrum, proved that dyestuff H8 has stronger absorption peak in 350～600 wavelength regions, see accompanying drawing 13.
(iii) (operation viii)-(x), the result has proved that equally target dyestuff H8 can produce singlet oxygen under 473nm or 532nm laser radiation, sees accompanying drawing 14, and superoxide anion with reference to embodiment 1.
It is contemplated that,, describe more than those skilled in the art also can utilize in the wideest scope even without other details.Therefore, preferred embodiment only should be considered as illustrative open, must not be considered as the qualification of any way.
Claims (10)
1. the compound of a logical formula I:
Wherein: R
1For-(C
2H
4O)
m-R
5Group;
R
2For methyl, ethyl or-(C
2H
4O)
n-R
6Group;
R
3For methyl, ethyl or-(C
2H
4O)
p-R
7Group;
R
4For methyl, ethyl or-(C
2H
4O)
q-R
8Group;
R
1, R
2, R
3And R
4It can be identical or different substituted radical;
Described-(C
2H
4O)
m-R
5M=3 in the group, 4,5,6,7 or 8; R
5Be methyl, ethyl, propyl group or sec.-propyl;
Described-(C
2H
4O)
n-R
6N=3 in the group, 4,5,6,7 or 8; R
6Be methyl, ethyl, propyl group or sec.-propyl;
Described-(C
2H
4O)
p-R
7P=3 in the group, 4,5,6,7 or 8; R
7Be methyl, ethyl, propyl group or sec.-propyl;
Described-(C
2H
4O)
q-R
8Q=3 in the group, 4,5,6,7 or 8; R
8Be methyl, ethyl, propyl group or sec.-propyl.
2. compound as claimed in claim 1, m wherein, n, p, q are 4 or 5; R
5, R
6, R
7, R
8Be methyl.
3. compound as claimed in claim 1, wherein R
3For-(C
2H
4O)
p-R
7Group.
4. compound as claimed in claim 1, wherein R
3, R
4Be identical substituting group.
5. the preparation method of a logical formula I compound,
Wherein: R
1For-(C
2H
4O)
m-R
5Group;
R
2For methyl, ethyl or-(C
2H
4O)
n-R
6Group;
R
3For methyl, ethyl or-(C
2H
4O)
p-R
7Group;
R
4For methyl, ethyl or-(C
2H
4O)
q-R
8Group;
R
1, R
2, R
3And R
4It can be identical or different substituted radical;
Described-(C
2H
4O)
m-R
5M=3 in the group, 4,5,6,7 or 8; R
5Be methyl, ethyl, propyl group or sec.-propyl;
Described-(C
2H
4O)
n-R
6N=3 in the group, 4,5,6,7 or 8; R
6Be methyl, ethyl, propyl group or sec.-propyl;
Described-(C
2H
4O)
p-R
7P=3 in the group, 4,5,6,7 or 8; R
7Be methyl, ethyl, propyl group or sec.-propyl;
Described-(C
2H
4O)
q-R
8Q=3 in the group, 4,5,6,7 or 8; R
8Be methyl, ethyl, propyl group or sec.-propyl,
This method comprises:
(i) in ethanol-water solution under the basic catalyst condition, with cyclopentanone and logical formula II compound
Wherein: R
1, R
2Define as the front,
Or with logical formula III compound
R wherein
11Be methyl or ethyl; R
12Be methyl or ethyl,
The logical formula IV intermediate product that obtains is collected in reaction
Wherein, R
3, R
4Define as the front,
The logical formula IV intermediate product that (ii) will obtain thus under the basic catalyst condition, reacts with logical formula II compound in alcohol solvent,
(iii) collect the logical formula I compound that obtains.
6. the preparation method of logical formula I compound as claimed in claim 5, the building-up reactions of its formula of (IV) intermediate product is carried out under condition of ice bath.
7. the preparation method of a general formula (V) compound,
Wherein: R
1For-(C
2H
4O)
m-R
5Group;
R
2Be selected from methyl, ethyl or-(C
2H
4O)
n-R
6Group;
Described-(C
2H
4O)
m-R
5M=3 in the group, 4,5,6,7 or 8; R
5Be selected from methyl, ethyl, propyl group or sec.-propyl;
Described-(C
2H
4O)
n-R
6N=3 in the group, 4,5,6,7 or 8; R
6Be selected from methyl, ethyl, propyl group or sec.-propyl,
This method comprises:
(i) in alcohol solvent under the basic catalyst condition, with the reaction of cyclopentanone and logical formula II compound,
Wherein: R
1, R
2Define as the front,
(ii) collect general formula (V) compound that obtains.
8. the photo-dynamical medicine that is active ingredient with logical formula I compound as claimed in claim 1.
9. the single photon photo-dynamical medicine that is active ingredient with logical formula I compound as claimed in claim 1.
10. with the purposes of logical formula I compound as claimed in claim 1 in preparation single photon photo-dynamical medicine.
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| CN107189489A (en) * | 2017-06-20 | 2017-09-22 | 武汉工程大学 | It is a kind of that there is luminescent dye molecule of biological polar sensitive and preparation method thereof |
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| CN106467487A (en) * | 2015-08-19 | 2017-03-01 | 中国科学院理化技术研究所 | A kind of water-soluble cationic benzal cycloalkane ketone photosensitizer and preparation method thereof and the application in the sterilizing of light power |
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| CN107198774A (en) * | 2016-03-16 | 2017-09-26 | 中国科学院理化技术研究所 | Folate-targeted fat water amphiphilic benzal cycloalkane ketone sensitising agent, preparation and its application in optical dynamic therapy photosensitive drug is prepared |
| CN107200694A (en) * | 2016-03-16 | 2017-09-26 | 中国科学院理化技术研究所 | A kind of water soluble anion benzal cycloalkane ketone sensitising agent, preparation method and the application in light power anti-microbial infection |
| CN107198774B (en) * | 2016-03-16 | 2021-02-12 | 中国科学院理化技术研究所 | Folic acid targeted lipid-water amphiphilic benzylidene cycloparaffinone photosensitizer, preparation method and application thereof in preparation of photosensitive drugs for photodynamic therapy |
| CN107189489A (en) * | 2017-06-20 | 2017-09-22 | 武汉工程大学 | It is a kind of that there is luminescent dye molecule of biological polar sensitive and preparation method thereof |
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